Canonical Wnt pathway signaling suppresses VCAM-1 expression by marrow stromal and hematopoietic cells.
OBJECTIVE
The Wnt family may contribute to hematopoietic stem cell (HSC) maintenance in bone marrow, but many questions remain concerning mechanisms. Vascular cell adhesion molecule-1 (VCAM-1) is expressed in cellular compartments of the bone marrow and might contribute to the HSC niche, but mechanisms concerning its constitutive expression are largely unknown. We now explore the influence of Wnt signaling on cellular adhesion molecule expression by bone marrow stromal and hematopoietic cells.


METHODS
Recombinant Wnt ligands, retroviral Wnt transductions and cocultures with Wnt-secreting cells were used to analyze the effect of Wnt on adhesion molecule expression by stromal and hematopoietic cells. In vivo experiments were also done to assess the ability of Wnt3a-induced, VCAM-1 deficient hematopoietic cells to engraft bone marrow.


RESULTS
We now report that the beta-catenin-dependent canonical Wnt signaling pathway negatively regulates VCAM-1 expression on two types of bone marrow cells. Wnt pathway inhibitors, Axin (intracellular) or Dickkopf-1 (extracellular) blocked the regulation of VCAM-1 by diffusible Wnt3a. Interestingly, lipopolysaccharide restored a substantial degree of VCAM-1 expression, suggesting functional cross-talk between Wnt and TLR4 signaling pathways. Decreasing VCAM-1 on HSC-enriched Lin(-) Sca-1(+) c-Kit(Hi) Thy1.1(Lo) cells by exposure to Wnt3a did not prevent their successful transplantation.


CONCLUSIONS
Our results suggest that cells comprising and residing in the HSC niche can respond to Wnt ligands and extinguish VCAM-1. This response may be important for export of hematopoietic cells. Given the known contribution of VCAM-1 to inflammation, this may represent a new avenue for therapeutic intervention.
Malhotra
Sachin
S
Immunobiology and Cancer Program, Oklahoma Medical Research Foundation and the Department of Microbiology and Immunology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA.
Kincade
Paul W
PW
D000818:Animals; D060466:Axin Protein; D001853:Bone Marrow / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000502:physiology*; D006412:Hematopoietic Stem Cells / Q000378:metabolism*; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D017154:Stromal Cells / Q000378:metabolism; D014161:Transduction, Genetic; D019010:Vascular Cell Adhesion Molecule-1 / Q000096:biosynthesis* / Q000235:genetics; D051153:Wnt Proteins / Q000235:genetics / Q000378:metabolism*; D060508:Wnt3 Protein; D060509:Wnt3A Protein; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism
D060466:Axin Protein; C501127:Dkk1 protein, mouse; D036341:Intercellular Signaling Peptides and Proteins; D011994:Recombinant Proteins; D012097:Repressor Proteins; D019010:Vascular Cell Adhesion Molecule-1; D051153:Wnt Proteins; D060508:Wnt3 Protein; D060509:Wnt3A Protein; C555511:Wnt3a protein, mouse; D051176:beta Catenin